Conventional subcutaneous routes of insulin administration are increasingly being researched to be replaced by oral drug delivery mechanisms that would not alter their physiological clinical activity. Problems confronted in this field of art in designing an effective oral drug delivery system for biological macromolecules has been mainly attributed to its susceptibility to enzymatic degradation and low epithelial permeability. Further, the structure and conformation of insulin are easily altered when exposed to formulation and process conditions leading to a loss of biological activity. Some of the approaches to combat these limitations involved the use of insulin analogs, administration of peptides such as amylin, glucagon-like peptide, C-peptides, inhaled forms, intranasal forms which have not satisfactorily addressed the limitations of bioavailability individually.
There is a need in the art for pharmaceutically acceptable complexes including derivatized insulin conjugates having increased bioavailability or other improved pharmaceutical attributes relative to the existing conjugates. Furthermore these improved conjugates need to be delivered in the form of a stable and improvised formulation that easily maximizes the benefits of oral delivery of proteins. The instant invention applies a combined approach of an improved insulin conjugate with increased bioavailability and an improved formulation to address the limitations of insulin delivery.
Examples of insulin compounds include human insulin, lyspro insulin, des30 insulin, native proinsulin, artificial proinsulins, etc. The cation component may, for example, be a divalent metal cation selected from the group consisting of Zn++, Mn++, Ca++, Fe++, Ni++, Cu++, Co++ and Mg++. The cation-insulin compound conjugate complexes also include a modifying moiety coupled (e g., covalently or ionically) to the insulin compound to provide an insulin compound conjugate. Further, the modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound, and the water solubility of the insulin compound conjugate is decreased by the addition of zinc. The modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound; the water solubility of the insulin compound conjugate is decreased by the addition of zinc; and water solubility of the complex is greater than the water solubility of insulin compound.
Examples of suitable modifying moieties and insulin conjugates useful in the preparation of compositions can be found in U.S. Pat. Nos. 7,060,675, 6,303,569, 6,214,330, 6,113,906, 5,985,263, 5,900,402, 5,681,811, 5,637,749, 5,612,640, 5,567,422, 5,405,877, 5,359,030 the entire disclosures of which are incorporated herein by reference. Additional examples of such cation-insulin compound conjugate complexes are provided in US patent applications US2003/083232, US 2006/0019873 and US2006/0019874.
In contrary to the existing prior art, the compounds of the present invention exhibit reduced mitogenic potential which is almost three fold lower than that of Insugen®.
Insulin binds and activates its cognate, the insulin receptor (IR) with sub-nanomolar affinity. Insulin also binds the structurally related Insulin growth factor receptor (IGFR) but with 1000 fold lower affinity than the insulin receptor. At physiological insulin concentrations the IGFR therefore does not play any role in mediating the effects of insulin. However at very high insulin concentrations (diabetic patients receiving insulin) it exerts mitogenic affects via the IGFR which transmits growth stimuli more efficiently than the insulin receptor (Lammers R, et al., EMBO 1989).
One of the earlier identified insulin analogs with modification at the aspartic acid B10 residue was aimed at providing a fast acting insulin effect, however the modification in turn led to a significant increase in the mitogenicity of that analog [Drejer, K., The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake. Diabetes Metab Rev, 1992. 8(3): p. 259-85]. A study was performed to study binding of several insulin analogs to the insulin growth factor-1 (IGF-1) receptor and the insulin receptor. The binding constants were measured and correlated to the metabolic and mitogenic potency of the insulin analogs studied [Kurtzhals, P., et al., Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes, 2000. 49(6): p. 999-1005.] As per the studies conducted, compared to regular insulin, insulin lispro, insulin aspart, and insulin glargine had minimal change in binding to the insulin receptor, whereas insulin detemir was significantly lower. Each of these analogs had similar or increased dissociation rates from the IGF receptor, which was correlated to their mitogenic behavior.
The mitogenic potency of proteins/peptides and their conjugates, cation-peptide conjugate complexes, cation-insulin conjugate complexes are of prime concern attributed to the risk of increased mitogenicity and growth of human mammary epithelial cells. Studies have proven that the binding of IGF-1 of insulin aspart was similar to that of native human insulin. Insulin lispro and insulin glargine had 1.5 to 6.5 fold increase in binding affinity to the IGF-1 receptor, respectively implying that insulin glargine has a significantly greater mitogenic response.
The long term effects of the mitogenic properties of insulin analogs, their conjugates, cation-peptide conjugate complexes, cation-insulin conjugate complexes continues to be an important factor to be considered. The Points to consider document CPMP/SWP/372/01 on the non-clinical assessment of the carcinogenic potential of insulin analogues states: “Native human insulin has, in addition to its metabolic actions, a weak mitogenic effect. This effect has become important for the safety of insulin analogues, since structural modifications of the insulin molecule could increase the mitogenic potency, possibly resulting in growth stimulation of pre-existing neoplasms.” “Although enhanced insulin-like growth factor 1 (IGF-1) receptor activation and/or aberrant signalling through the insulin receptor have been implicated, the mechanism(s) responsible for the mitogenic activity of insulin analogues remain to be clarified.”
As an evidence that IGF-1 promotes colonic-, breast-, prostatic-, and lung cancer growth is accumulating, there exists a need for the development of proteins/peptides and their conjugates, cation-peptide conjugate complexes, cation-insulin conjugate complexes with minimal mitogenic risk which is assessed in a cell proliferation assay and that may be termed safe for long term therapy.
Current invention relates to protein/peptides, their conjugates, and/or cation-polypeptide conjugate complexes displaying three folds lower mitogenic properties in comparison to Insugen). Further aspects of the present invention are directed to the fact that excipients in the drug product does not statistically impact the mitogenic potency characteristics of the drug substance.
Another aspect of the invention relates to improvised pharmaceutical compositions permitting ingestion via oral delivery of proteins/peptides or their conjugates, and/or cation-insulin conjugate complexes demonstrating desirable pharmacokinetic profiles and potency in efficacy models of diabetes in dogs and humans.
WO00/50012 discloses solid oral dosage forms comprising a drug and an enhancer, wherein the enhancer is a salt of a medium chain fatty acid with a carbon chain length of about 6-20 carbon atoms. US2006/0018874 cover a solid pharmaceutical composition formulated for oral administration by ingestion, having 0.1 to 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated fatty acids and/or salts and a therapeutic agent.
Notwithstanding the foregoing, there still exists a need for manufacture of viable oral insulin formulations that can overcome problems associated with loss of biological activity during manufacture and at the same time exhibit enhanced resistance to enzymatic degradation in-vivo post ingestion. The present invention addresses both requirements. Thereby, the invention addresses the problems confronted in the art to design a highly effective oral insulin-conjugate drug delivery mechanism.
The invention exhibits various advantages with respect to the dosing and convenient method of administration. The invention constitutes yet another advantage over the prior art compositions as the inventors propose that the claimed rationally designed oral formulation of IN-105 with measured components of other excipients and the process of manufacturing the orally administrable tablets are easily scalable. Further, attributed to this rationally designed oral formulation and the process of making the same, the scalability factor does not impact the in-vivo drug performance or its in-vivo release profile.
Currently available oral insulin formulations exhibit low levels of stability precluding possibilities of oral administration of such therapeutics. One of the most significant aspect of the present invention is characterized in the fact that the instant oral insulin formulation is stable over a range of temperature without adversely impacting various parameters of the tablet stability such as hardness, disintegration time, accumulation of high molecular weight impurities and dissolution rate. The tablets thus made show excellent stability even under accelerated stability conditions of 40° C./75% relative humidity. The inherent stable characteristics of the molecule and the manufacturing methods attribute to the stable nature of the formulation.
Another aspect of the invention relates to improved pharmaceutical compositions of cation-insulin conjugate complexes prepared by a scalable spray drying procedure said process comprising steps of preparing an aqueous suspension of the cation-insulin conjugate complex and at least one fatty acid component with optionally one or more pharmaceutically acceptable excipients.
In a typical process for fine particles using a spray drying process, material, such as the ingredient which is intended to form the bulk of the particle is dissolved in an appropriate solvent to form a solution. Alternatively, the material intended to be spray dried can be suspended or emulsified in a non-solvent to form a suspension or emulsion. Other components, such as drugs, pharmaceutically acceptable excipients or pore forming agents optionally are added at this stage. The solution then is atomized to form a fine mist of droplets. The droplets immediately enter a drying chamber where they contact a drying gas. The solvent is evaporated from the droplets into the drying gas to solidify the droplets, thereby forming particles. These particles then are separated from the drying gas and collected.
In scaling up such a spray drying process, for example from the laboratory or pilot plant scale to the commercial plant scale, certain problems may be encountered. If the drying rate and drying capacity are not adequately optimized undesirable problems may be faced such as improper drying of solvent particles, reduced product yield, purity etc. On the other hand increasing the drying rate that is inadequately scaled may result in unsuitable particle morphology and/or size distribution for some product particles, such as those having critically defined performance specifications. More significantly, it may also alter the way in which the solid-forming material precipitates as the solvent is evaporated, thereby changing the structure (e.g., porosity) of the particle to be out of specification standards, rendering the particle unable to properly contain and deliver a diagnostic or therapeutic agent.
There is therefore a need in the art for an improved spray-drying process that results in the production of homogenous solid amorphous dispersions at high purity with improved flow characteristics, improved content uniformity, and improved collection efficiency.
One of the objects of the present invention is to provide spray dried compositions of cation-insulin conjugate complexes involving a drying process that provides improved drying of particles without detrimentally impacting the product purity, yield and stability. The current process yields homogeneous spray dried solid particles of the target therapeutic agent that is further formulated with other requisite excipients to yield an oral pharmaceutical compositions of cation-insulin conjugate complexes.
Other objects and advantages of the present invention will be more fully apparent to those of ordinary skill in art, in light of the ensuing disclosure and appended claims.